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The treatment of bone metastases is a thorny issue. Immunotherapy may be one of the few hopes for patients with unresectable bone metastases. Immune checkpoint inhibitors are the most commonly used immunotherapy drugs currently. In this review, the characteristics and interaction of bone metastases and their immune microenvironment were systematically discussed, and the relevant research progress of the immunological mechanism of tumor bone metastasis was reviewed. On this basis, we expounded the clinical application of immune checkpoint inhibitors for bone metastasis of common tumors, including non-small-cell lung cancer, renal cell carcinoma, prostate cancer, melanoma, and breast cancer. Then, the deficiencies and limitations in current researches were summarized. In-depth basic research on bone metastases and optimization of clinical treatment is needed.

In this paper, we reported a rapid and simple approach to synthesize molecularly imprinted polymers (MIPs) materials for sensing of 2,4-dichlorophenoxyacetic acid (2,4-D) residues in environmental water and mixed juice. Initially, MIPs materials were prepared via visible light-initiated reversible addition-fragmentation chain transfer (RAFT) emulsion polymerization at ambient temperature using 2,4-D and its analogs as template molecules, in which 4-vinyl pyridine (4-VP), ethylene glycol dimethacrylate (EGDMA), (2,4,6-trimethylbenzoyl) diphenylphosphine oxide (TPO), 2-(((dodecylthio)carbonothioyl)thio)-2-methylpropanoic acid (DDMAT) were functional monomer, cross-linker, visible light initiator and RAFT agent, respectively. Then, the morphologies of the MIPs materials were characterized by FT-IR, SEM and DLS. The results showed that the MIPs materials were well-distributed spherical particles with sizes ranging from 1 to 2 μm. Furthermore, a four-channel MIPs sensor array included four polymer microspheres with a fluorescent dye displacement procedure was developed to distinguish the templates and their chemical analogs at the ppm concentration level. With the support of principal component analysis and hierarchical cluster analysis, the four-channel MIPs sensor array proves to be a simple and effective method to recognize and distinguish the templates and nontemplates in aqueous solution with 100% accuracy. Finally, the four-channel MIPs sensor array was also found to have satisfactory accuracy in monitoring 2,4-D contaminated environmental water and mixed juice.

Nicosulfuron, a widely utilized herbicide, is detrimental to some maize varieties due to their sensitivity. Developing tolerant varieties with resistance genes is an economical and effective way to alleviate phytotoxicity. In this study, map-based cloning revealed that the maize resistance gene to nicosulfuron is Zm00001eb214410 ( CYP81A9 ), which encodes a cytochrome P450 monooxygenase. qRT- PCR results showed that CYP81A9 expression in the susceptible line JS188 was significantly reduced compared to the resistant line B73 during 0-192 hours following 80 mg/L nicosulfuron spraying. Meanwhile, a CYP81A9 overexpression line exhibited normal growth under a 20-fold nicosulfuron concentration (1600 mg/L), while the transgenic acceptor background material Zong31 did not survive. Correspondingly, silencing CYP81A9 through CRISPR/Cas9 mutagenesis and premature transcription termination mutant EMS4-06e182 resulted in the loss of nicosulfuron resistance in maize. Acetolactate Synthase (ALS), the target enzyme of nicosulfuron, exhibited significantly reduced activity in the roots, stems, and leaves of susceptible maize post-nicosulfuron spraying. The CYP81A9 expression in the susceptible material was positively correlated with ALS activity in vivo . Therefore, this study identified CYP81A9 as the key gene regulating nicosulfuron resistance in maize and discovered three distinct haplotypes of CYP81A9 , thereby laying a solid foundation for further exploration of the underlying resistance mechanisms.

Background To compare proprioception recovery after anterior cruciate ligament reconstruction (ACLR) with a hamstring tendon autograft versus the artificial Ligament Advanced Reinforcement System (LARS). Material and methods Forty patients (9 females, 31 males) with anterior cruciate ligament (ACL) rupture were enrolled in this prospective study. Patients were randomized to two groups, 1) ACLR using a hamstring tendon autograft ( n  = 20) or 2) ACLR using artificial LARS ( n  = 20). Proprioception was assessed with knee joint position sense (JPS) passive-passive test at 45° and 75° flexions, with the contralateral healthy knee as a control baseline to calculate the JPS error. Knee JPS absolute error was used as the main outcome variable and defined as the absolute difference between the reproduction and target angles. Results JPS error in both groups at 3 months after ACLR was significantly higher than that at 12 months. However, no significant difference in JPS error was detected between the LARS and autograft groups at either 3 or 12 months after ACLR. Analyzing JPS data by grouping patients according to whether ACLR was performed more or less than 1 year following injury regardless of graft type showed a statistically significant difference between the groups at 3 months, but not at 12 months, after ACLR. Patients receiving the graft within 1 year of injury had a lower JPS error than those receiving the graft more than 1 year after injury at 3 months. No complications were associated with either ACLR method. Conclusion ACLR with a hamstring tendon autograft or LARS artificial graft is similarly safe and effective for recovering knee proprioception.

Background Limb salvage reconstruction for pelvic tumors, especially periacetabular tumors, is challenging. We combined the use of dual mobility bearing and 3D-printed hemipelvic prosthesis to improve function and reduce the probability of complications after hemi-pelvic resection in patients with primary acetabular malignancy. The purpose of this study was to evaluate the efficacy and safety of this combination. Methods Between October 2011 and May 2021, 11 patients with malignancies involving the acetabulum received hemipelvic replacement with a 3D-printed prosthesis and dual mobility bearing. Follow‐up of postoperative survival, complications, and Musculoskeletal Tumor Society 93 (MSTS-93) lower limb functional scores were carried out. A finite element model of the postoperative pelvis was developed and input into the finite element analysis software. The Von Mises equivalent stress formula was used to analyze the stress distribution of each part of the pelvis under one gait cycle and the stress distribution at different angles of the hip joint. Results By the last follow-up, 9 of the 11 patients (81.8%) were still alive, and 2 patients had local tumor recurrence. The complications including 1 deep infection and 1 dislocation of the artificial joint. Excluding 1 amputation patient, the average score of the remaining 8 patients at the last follow-up was 21.4/30 (71.3%) on the MSTS-93. In the reconstructed pelvis, stress distributions were concentrated on the junction between hemipelvic prosthesis and screw and iliac bone on the resected side, and between femoral prosthesis stem and femoral bulb, while the stress of polyethylene lining was small. Before impact, the polyethylene lining will rotate at a small angle, about 3°. The inner stress of polyethylene liner is greater than the outer stress in all conditions. The polyethylene liner has no tendency to slide out. Conclusion Pelvic tumor resection and reconstruction using 3D-printed hemipelvic prosthesis combined with dual mobility bearing was an effective treatment for pelvic tumors. Our patients achieved good early postoperative efficacy and functional recovery. The dual mobility bearing is beneficial to prevent dislocation, and the mechanical distribution and wear of the prosthesis are acceptable.

Background Cuscutae Semen (CS) has been prescribed in traditional Chinese medicine (TCM) for millennia as an aging inhibitor, an anti-inflammatory agent, a pain reliever, and an aphrodisiac. Its three main forms include crude Cuscutae Semen (CCS), wine-processed CS (WCS), and stir-frying-processed CS (SFCS). Premature ovarian insufficiency (POI) is a globally occurring medical condition. The present work sought a highly efficacious multi-target therapeutic approach against POI with minimal side effects. Finally, it analyzed the relative differences among CCS, WCS and SFCS in terms of their therapeutic efficacy and modes of action against H 2 O 2 -challenged KGN human granulosa cell line. Methods In this study, ultrahigh-performance liquid chromatography (UPLC)-Q-ExactiveTM Orbitrap-mass spectrometry (MS), oxidative stress indices, reactive oxygen species (ROS), Mitochondrial membrane potential (MMP), real-time PCR, Western blotting, and molecular docking were used to investigate the protective effect of CCS, WCS and SFCS on KGN cells oxidative stress and apoptosis mechanisms. Results The results confirmed that pretreatment with CCS, WCS and SFCS reduced H 2 O 2 -induced oxidative damage, accompanied by declining ROS levels and malondialdehyde (MDA) accumulation in the KGN cells. CCS, WCS and SFCS upregulated the expression of antioxidative levels (GSH, GSH/GSSG ratio, SOD, T-AOC),mitochondrial membrane potential (MMP) and the relative mRNA(Nrf2, Keap1, NQO-1, HO-1, SOD-1, CAT). They inhibited apoptosis by upregulating Bcl-2, downregulating Bax, cleaved caspase-9, and cleaved caspase-3, and lowering the Bax/Bcl-2 ratio. They also exerted antioxidant efficacy by partially activating the PI3K/Akt and Keap1-Nrf2/HO-1 signaling pathways. Conclusions The results of the present work demonstrated the inhibitory efficacy of CCS, WCS and SFCS against H 2 O 2 -induced oxidative stress and apoptosis in KGN cells and showed that the associated mechanisms included Keap1-Nrf2/HO-1 activation, P-PI3K upregulation, and P-Akt-mediated PI3K-Akt pathway induction.

Chronic obstructive pulmonary disease (COPD) is a disease with a complex etiology. The secretion of inflammatory factors, such as IL-1β and oxidative stress, plays an important role in the pathogenesis of COPD. The aim of this paper is to investigate the changes in the redox protein thioredoxin (TRX) in COPD and the role TRX plays in IL-1β release. We analyzed data from single-cell RNA sequencing (scRNA-seq) of COPD lung tissue in the GEO database. Changes in TRX expression levels and activity were assessed by protein activity analysis of alveolar macrophages(AM). Using Monocle2 and molecular dynamics(MD) to analyze which pathways through TRX achieves regulation of the inflammatory response. The analytical results were subsequently validated by constructing vivo and vitro models. AM that specifically synthesize IL-1β were identified by scRNA-seq. No change in TRX expression levels and decreased protein antioxidant activity in IL-1β+ AM with COPD. We confirmed an increase in oxidized TRX (oxTRX) and a decrease in reduced TRX (reTRX) in COPD mouse model and THP-1 cell model. The decrease in reTRX was accompanied by the upregulation of NLRP3 activity, which played a catalytic role in the synthesis of IL-1β in this subgroup. This was subsequently confirmed in a cigarette smoke-induced THP-1 cell model. A decrease in reTRX level accompanied by an upregulation of NLRP3 activity, which plays a facilitating role in the synthesis of IL-1β. We determined that reTRX reduction was followed by depolymerization of thioredoxin-interacting protein (TXNIP) through MD and immune co-precipitation (CO-IP). Then TNXIP interacted with NLRP3 and up-regulate NLRP3 activity, which in turn promoted IL-1β release. Our study shows that the reTRX is abnormally altered in COPD and leads to the upregulation of NLRP3 activity in AM to enhance IL-1β production.

Promoting the M2 phenotype polarization of microglia is of great significance in alleviating hypoxic-ischemic encephalopathy (HIE). The umbilical artery blood sample was collected to evaluate the expression of cGAS, and the aberrant expressed cGAS was verified in the oxygen glucose deprivation (OGD) microglia which was established to mimic HIE in vitro. Then the regulating role of cGAS on the transformation of microglia M2 phenotype polarization and glycolysis was investigated. Moreover, the lactylation of cGAS in OGD treated microglia was evaluated by western blot. cGAS was found to be highly expressed in umbilical artery blood of HIE group, and OGD treated microglia. OGD interference activated microglia into M1 phenotype by enhancing CD86 and suppressing CD206 levels; meanwhile, the microglia in OGD group highly expressed IL-1β, iNOS and TNF-α, and lowly expressed IL-4, IL-10, and Arg-1. Inhibition of cGAS promotes the transformation of microglia from M1 to M2 phenotype. Meanwhile, OGD increased ECAR and decreased OCR to regulate glycolysis, cGAS deficiency inhibits glycolysis in OGD treated microglia. Moreover, the pan lysine lactylation (Pan-Kla) levels and lactated cGAS levels in microglia were upregulated in the OGD group. Lactate reversed the effects of cGAS knockdown on microglia polarization and glycolysis. The present study reveals that the cGAS-mediated neuron injury is associated with high level of cGAS lactylation. Inhibition of cGAS promotes the M2 phenotype polarization of microglia and suppress glycolysis. Thereby, targeting cGAS provides a new strategy for the development of therapeutic agents against HIE.

Bone marrow mesenchymal stem cell (BMSC) is previously reported to present a certain effect on treating spinal cord injury (SCI), while the underlying mechanism is largely uncovered. Therefore, the current study aimed to investigate the involvement of exosome-delivered circRNA profile in the BMSC’s effect on pyroptosis for SCI treatment. H 2 O 2 treated rat primary neurons were cultured with normal medium, BMSC, BMSC plus GW4869, and BMSC-derived exosome, respectively, then inflammasome-related pyroptosis markers, and circRNA profiles were detected. Subsequently, circ_003564-knockdown BMSC exosome was transfected into H 2 O 2 treated rat primary neurons and NGF-stimulated PC-12 cells. Furthermore, in vivo validation was conducted. BMSC and BMSC-derived exosome both decreased inflammasome-related pyroptosis markers including cleaved caspase-1, GSDMD, NLRP3, IL-1β, and IL-18 in H 2 O 2 -treated neurons, while exosome-free BMSC (BMSC plus GW4869) did not obviously reduce these factors. Microarray assay revealed that BMSC (vs. exosome-free BMSC) and BMSC-derived exosome (vs. normal medium) greatly regulated circRNA profiles, which were enriched in neuroinflammation pathways (such as neurotrophin, apoptosis, and TNF). Among three functional candidate circRNAs (circ_015525, circ_008876, and circ_003564), circ_003564 was most effective to regulate inflammasome-related pyroptosis. Interestingly, circ_003564-knockdown BMSC exosome showed higher expression of inflammasome-related pyroptosis markers compared to negative-control-knockdown BMSC exosome in H 2 O 2 treated primary neurons/NGF-stimulated PC-12 cells. In vivo, BMSC exosome improved the function recovery and decreased tissue injury and inflammasome-related pyroptosis in SCI rats, whose effect was attenuated by circ_003564 knockdown transfection. BMSC exosome attenuates inflammasome-related pyroptosis via delivering circ_003564, contributing to its treatment efficacy for SCI.

Objective: Chronic obstructive pulmonary disease (COPD) is a disease with a complex etiology. The secretion of inflammatory factors, such as IL-1[beta] and oxidative stress, plays an important role in the pathogenesis of COPD. The aim of this paper is to investigate the changes in the redox protein thioredoxin (TRX) in COPD and the role TRX plays in IL-1[beta] release. Methods: We analyzed data from single-cell RNA sequencing (scRNA-seq) of COPD lung tissue in the GEO database. Changes in TRX expression levels and activity were assessed by protein activity analysis of alveolar macrophages(AM). Using Monocle2 and molecular dynamics(MD) to analyze which pathways through TRX achieves regulation of the inflammatory response. The analytical results were subsequently validated by constructing vivo and vitro models. Results: AM that specifically synthesize IL-1[beta] were identified by scRNA-seq. No change in TRX expression levels and decreased protein antioxidant activity in IL-1[beta]+ AM with COPD. We confirmed an increase in oxidized TRX (oxTRX) and a decrease in reduced TRX (reTRX) in COPD mouse model and THP-1 cell model. The decrease in reTRX was accompanied by the upregulation of NLRP3 activity, which played a catalytic role in the synthesis of IL-1[beta] in this subgroup. This was subsequently confirmed in a cigarette smokeinduced THP-1 cell model. A decrease in reTRX level accompanied by an upregulation of NLRP3 activity, which plays a facilitating role in the synthesis of IL-1[beta]. We determined that reTRX reduction was followed by depolymerization of thioredoxin-interacting protein (TXNIP) through MD and immune co-precipitation (CO-IP). Then TNXIP interacted with NLRP3 and up-regulate NLRP3 activity, which in turn promoted IL-1[beta] release. Conclusion: Our study shows that the reTRX is abnormally altered in COPD and leads to the upregulation of NLRP3 activity in AM to enhance IL-1[beta] production. Keywords: chronic obstructive pulmonary disease, single-cell RNA sequencing, alveolar macrophages, thioredoxin, inflammations